Sodium Hydroxide → Petesicatib

HRID 2402918Notes

Reaction equation

HRID 2402918 reaction equation
[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)=[CH:17][C:16]=3[C:27]([F:30])([F:29])[F:28])[CH2:11][N:10]2[C:31]([C:33]2([C:36]([F:39])([F:38])[F:37])[CH2:35][CH2:34]2)=[O:32])=[O:8])[CH2:5][CH2:4]1)#[N:2].[OH2:40].[OH2:41].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>C(#N)C.O>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)=[CH:17][C:16]=3[C:27]([F:30])([F:29])[F:28])(=[O:41])=[O:40])[CH2:11][N:10]2[C:31]([C:33]2([C:36]([F:39])([F:38])[F:37])[CH2:34][CH2:35]2)=[O:32])=[O:8])[CH2:4][CH2:5]1)#[N:2]

Participants

7

Reactant 4

HCID 14798Sodium HydroxideHCID 656671Sodium PyrosulfiteHCID 21894687Magnesium 2-(dioxidan-2-ide-1-carbonyl)benzoate--water (1/1/6)2×HCID 86684922HCID 86684922, compound

Product 1

HCID 59543597PetesicatibYield 76%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
50 °C

Procedure

(2S,4R)-4-[4-(1-Methyl-1H-pyrazol-4-yl)-2-trifluoromethyl-phenylsulfanyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (crude product, 97.6% purity, 64.0 g, 109 mmol) was dissolved in acetonitrile (480 mL) and magnesium monoperoxyphthalate hexahydrate (76.0 g, 154 mmol) was added. The resulting white suspension was stirred for 5 h at 50° C. After that, a suspension of magnesium monoperoxyphthalate hexahydrate (76.0 g, 154 mmol) in acetonitrile (150 mL) was added and the mixture was stirred for further 16 h at 50° C. After cooling to 20° C., water (480 mL) and a solution of sodium metabisulfite in water (40% w/w, 56.8 mL, 109 mmol) were added. The mixture was basified to pH 8 by addition of an aqueous sodium hydroxide solution (3 M, ca. 290 mL), extracted with dichloromethane (1 L), the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution (1 L) and concentrated in vacuo. The residue was dissolved in dichloromethane (300 mL) and filtered to remove solid impurities. The solvent of the filtrate was exchanged to ethanol by continuous distillation while keeping the volume constant (ca. 750 mL ethanol used). The desired product started to crystallize. The resulting suspension was stirred for 12 h at 0° C., filtered, the precipitate was washed with cold ethanol (50 mL) and dried in vacuo at 45° C. to obtain the title compound as white crystals (50.0 g, 74.9%). MS (ESI & APCI): m/z=604.1 [M+H]+, 621.1 [M+NH4]+. 1H NMR (CDCl3, 600 MHz): δ 1.10-1.22 (m, 2H), 1.30-1.35 (m, 1H), 1.35-1.41 (m, 1H), 1.45-1.59 (m, 4H), 2.22-2.28 (m, 1H), 2.84 (ddd, J=5.9 Hz, 8.0 Hz, 14.3 Hz, 1H), 3.84 (dd, J=7.1 Hz, 13.2 Hz, 1H), 4.00 (s, 3H), 4.08-4.14 (m, 1H), 4.81 (d, J=13.3 Hz, 1H), 4.86 (dd, J=5.8 Hz, 8.6 Hz, 1H), 7.65 (bs, 1H), 7.80-7.83 (m, 2H), 7.89 (s, 1H), 7.99 (d, J=1.6 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H).

Workup

  1. additionwas added
  2. stirringthe mixture was stirred for further 16 h at 50° C
  3. temperatureAfter cooling to 20° C.
  4. extractionextracted with dichloromethane (1 L)
  5. washthe organic phase was washed with saturated aqueous sodium hydrogencarbonate solution (1 L)
  6. concentrationconcentrated in vacuo
  7. dissolutionThe residue was dissolved in dichloromethane (300 mL)
  8. filtrationfiltered
  9. customto remove solid impurities
  10. distillationThe solvent of the filtrate was exchanged to ethanol by continuous distillation
  11. customto crystallize
  12. stirringThe resulting suspension was stirred for 12 h at 0° C.
  13. filtrationfiltered
  14. washthe precipitate was washed with cold ethanol (50 mL)
  15. customdried in vacuo at 45° C.

Sources & evidence

ORD record
ord-2da6d3c8b19a422385f85efbb247371f
Source dataset
uspto-grants-2014_08
Patent number
US08796471B2

Reaction notes

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